SK66099A3 - Stabilised pharmaceutical compositions, with quinupristine and dalfopristine base and their preparation - Google Patents

Abstract

The invention concerns a stabilised pharmaceutical composition, with a combined quinopristine/dalfopristine base, containing at least a stoichiometric amount of methanesulphonic acid or hydrochloric acid and is characterised in that its pH is included in the {3.5; 5} interval.

Description

Technical field

The present invention relates to stabilized pharmaceutical compositions intended for parenteral administration of the quinupristine and dalfopristine components of the drug Synercid®.

BACKGROUND OF THE INVENTION

Patent application EP 248,703 discloses pristinamycin I derivatives of the general formula:

and combinations thereof with pristinamycin II derivatives of the general formula:

Quinupristine, a derivative of pristinamycin I, and dalfoprostin, a derivative of pristinamycin II, are components of Synercid®.

a 30/70 mixture whose antibacterial activity, particularly to vancomycin resistant bacteria, has been described in many publications [The Annals of Pharmacotherapy 29, 1022-1026 (1995); Microbial Drug Resistance 1: 223-234 (1995)].

The dissolution of the isolated components of quinupristine and dalfopristine can be achieved in the form of salts.

However, dissolution is particularly problematic in that it is necessary to find a satisfactory agent for all components. Further, it is necessary to ensure that the pharmaceutical compositions are characterized by such stability that the original dose of the active ingredient is maintained throughout the shelf life. The composition of stabilized pharmaceutical formulations containing a quinupristine / dalfopristin mixture, the stability of the solution and / or the lyophilisate prepared from the solutions raises serious problems of preparation and thus raises the question of the possibility of their use in the manufacture of a medicament which can be stored and thus sold. These problems occur in particular because a significant amount of decomposition impurities is generated.

SUMMARY OF THE INVENTION

It has now been found that pharmaceutical compositions containing a quinupristine / dalfopristine mixture can be stabilized using at least a stoichiometric amount of methanesulfonic acid or hydrochloric acid at a pH in the range of 3.5 to 5. Thus solutions based on methanesulfonic acid and hydrochloric acid with a pH in the range 3.5 to 5 are sufficiently stable for industrial production, and in this way, depending on the situation, lyophilisates, dilute solutions after lyophilization and / or frozen solutions can be prepared which are stable and can therefore be stored and marketed and / or used in treatment.

In particular, the stabilized pharmaceutical compositions of the present invention are aqueous solutions comprising:

Dalfopristin and quinupristin;

Methanesulfonic acid or hydrochloric acid in at least stoichiometric amounts relative to the total amount of dalfopristin and quinupristin;

If appropriate, an excess of methanesulfonic acid or hydrochloric acid to adjust the pH of the solution to between 3.5 and 5;

Optionally an isotonizing agent and / or other pharmaceutically acceptable excipient;

• the amount of water suitable to adjust the concentration of the solution.

The solutions thus obtained are advantageous because they are stabilized.

According to another embodiment of the invention, these compositions can be lyophilized using conventional procedures, after lowering the temperature and removing the water. They may be reintroduced into water before injection. According to other embodiments, they may also be frozen.

If the obtained compositions are lyophilized, they may be reconstituted in a suitable and pharmaceutically acceptable medium before administration. The lyophilisate can advantageously be reconverted, for example, into an injectable preparation or an infusion solution (in particular glucose or sodium chloride solution) in water. If the solution is frozen (for example a frozen bag), it may thaw before use. In another embodiment, the lyophilisate can be reconverted into a dilute solution (preferably containing less than 20 mg / ml of the active ingredient) and said solution is stored until use.

It will be understood that the present invention may also be applied to other soluble derivatives of pristinamycin. For example, it may also be applied to the derivatives described in EP 133,097, EP 135,410, EP 191,662 and EP 248,703.

The stabilized pharmaceutical compositions of the present invention preferably contain concentrations of the active ingredient quinupristine / dalfopristine in the range of 5 to 250 mg / ml or, in the case of a lyophilisate, a proportion of 5 to 95%, preferably 20 to 90%. It is clear that stabilized pharmaceutical compositions of lower concentration may also be prepared and used clinically; these compositions are also subject to the present invention.

The amount of acid depends on the amount of dalfopristin and quinupristin. It is determined so as to form at least a stoichiometric part and so as to obtain solutions having a pH in the range of 3.5 to 5.

According to a preferred embodiment of the invention, the pH of the starting solution is adjusted to a range of 3.5 to 4.5, preferably 3.5.

According to another preferred embodiment of the invention, in the case of a lyophilized composition, the pH of the solution to be lyophilized is adjusted to a range of 4.5 to 5.

Where the stabilized pharmaceutical compositions of the present invention contain a pharmaceutically acceptable adjuvant, the adjuvant may be an additional solvent, a stabilizer, a cryoprotective agent, a drying agent, a filler, and an isotonizing agent.

Without limiting the content, the additional solvent and dissolution aid may be selected from the group consisting of polyethylene glycols (polyethylene glycol 300 and 400), propylene glycol, ethanol, and surfactants such as polysorbate or polyoxyethylenated derivatives (cremophores); the fillers and cryoprotectants may preferably be selected from the group consisting of simple sugars (e.g. glucose, mannitol, fructose or sorbitol), disaccharides (e.g. sucrose, lactose, trehalose or maltose) or water-soluble polymers (e.g. dextrans, carboxymethylcellulose, polyvinylpyrrolidone or gelatin); in particular, stabilizing agents may be selected from the group consisting of antioxidants and the like; isotonizing agents may preferably be selected from the group consisting of glucose, sodium chloride, glycerol, sorbitol, mannitol, fructose or dextrans 40 and 70. If the pH of the solution is high (pH 5 or about 5) and is required to prepare a concentrated solution, a substance other than sodium chloride is used as the isotonizing agent.

The stabilized pharmaceutical compositions of the present invention are particularly intended for administration by the parenteral route. They can also be used for the oral, ocular or aural route, for administration or for topical application to the skin or mucosa.

The stabilized pharmaceutical compositions of the present invention are prepared by simultaneous or sequential dissolution of quinupristine, dalfopristine, methanesulfonic acid or hydrochloric acid in water and then adjusting the pH to a range.

3.5 to 5 and / or the addition of an isotonizing agent and / or the addition of another pharmaceutically acceptable additive, if appropriate, by lyophilization or freezing.

According to a preferred embodiment, the compositions of the present invention are prepared by dissolving the quinupristine component and then the dalfopristine component in water acidified with methanesulfonic acid or hydrochloric acid, then, if appropriate, adjusting the pH to a range of 3.5 to 5 and / or adding an isotonizing agent and / or by adding another pharmaceutically acceptable ingredient. If appropriate, they are lyophilized and / or frozen.

The solution is usually prepared at a temperature between 0 ° C and room temperature, preferably at lower temperatures, depending on the duration of the preparation and the pH. The operations are preferably carried out at a temperature below 10 ° C.

The stabilized pharmaceutical compositions of the present invention may optionally be sterilized. Sterilization is preferably performed by sterilizing filtration. The stabilized pharmaceutical compositions of the present invention in liquid, lyophilized or frozen form have advantageous optimal physicochemical stability that allows preservation for a period of time sufficient for their use in the preparation of a medicament that can be stored and thus marketed.

According to a preferred embodiment of the present invention, stabilized pharmaceutical compositions are those characterized by more than:

A 2% increase in the level of each major degradation impurity (A and B) after storage for 24 months at 4 ° C or for 12 months at 20 ° C in the case of lyophilisate;

A 2% increase in the level of each major degradation impurity (A and B) after storage for 18 hours at 0 to 6 ° C in the case of a concentrated solution before or after lyophilization;

A 2% increase in the level of each major degradation impurity (A and B) after storage for 3 months at -20 ° C in the case of a frozen formulation;

• a 5% increase in the level of each major degradation impurity (A and B) after storage for 6 hours at room temperature or 72 hours at 4 ° C in the case of diluted solution for infusion.

The invention is further illustrated by the following non-limiting examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1 liter of 125 mg / ml quinupristine / dalfopristine (30/70) solution, which is in the form of a methanesulfonic acid salt (ca.

16.7 mg / ml) at pH 4.75 is prepared by introducing 810 g of water for injectables into a dissolution vessel equipped with a cooling unit. The solution is cooled to between 0 and 6 ° C during processing, 16.4 g of methanesulfonic acid and then 37.5 g of quinupristine are added and these components are dissolved by mechanical stirring. Then 87.5 g of dalfopristin, which is also dissolved by mechanical stirring, is added. The pH is adjusted to 4.75 with 1N methanesulfonic acid solution. Make up the solution to 1 liter (1030 g) with water for injectables.

This solution is sterilized by sterilizing filtration (0.22 gm) and distributed into containers [500 mg quinupristine / dalfopristin (30/70) per container] and then lyophilized [freeze: temperature -30 to -50 ° C; a freezing rate of about 0.5 ° C / min; sublimation: pressure 50 Pa; second drying: about 3 Pa pressure, 40 ° C temperature].

The quality and stability during storage of the lyophilisate or reconstituted solution is determined by reverse-phase high-performance liquid chromatography (HPLC), which makes it possible to determine the content of dalfopristin and quinupristin and the content of degradation impurities.

HPLC analysis

Stationary phase Octadecylsilane inoculated silicone, Lichrospher-100 RP-18, 5 µm detection 254 nm UV Column dimensions 125 x 5 mm Column temperature Deň: 32 ° C Mobile phase Phosphate buffer pH 2,9 .......... 80 vol. Acetonitrile .......... 20 vol. Mobile phase Phosphate buffer pH 2,9 .......... 35 vol. Acetonitrile .......... 65 vol. gradient 0% mobile phase B to 66% mobile phase B for 42.5 min, then back to 0% mobile phase B for 1.5 min and 5 min equilibrium Mobile phase flow 1.1 ml / min

The HPLC analysis method makes it possible to determine the contents of quinupristine and dalfopristine to within 2% and to breakdown products to within 0.1%.

Two lyophilized doses of the quinupristine / dalfopristine mixture (30/70) placed in containers containing 500 mg of active ingredient (dose 1a and dose 1b) are processed according to the above method and their stability is studied when stored at 4 ° C for 2 years. The results of a stability study of each of these two doses show good retention of the active ingredients and very little degradation (see Tables I and II).

Quinupristine / dalfopristine (30/70) solutions are obtained by converting the lyophilisate again into 5.0 mL of 5% glucose. Under these conditions, the stability of the solution thus obtained (premix), which is observed for 60 minutes, is much more satisfactory and allows subsequent dilution in the infusion bag (see Table III).

Under the dilution conditions used prior to clinical administration (500 mg quinupristine / dalfopristin (30/70) in a 250 ml bag containing 5% glucose) the formulation provides satisfactory stability for at least 72 hours at 4 ° C or for 6 hours at 25 ° C (see Tables IV and V).

Results of stability tests of lyophilisate over 2 years:

Stability study of dose la for 24 months at 4 ° C

Table I

Dose la TO 3 months 6 months 9 months 12 months 18 months 24 months Test (mg / bottle) Dalfopristin 350 347 343 343 345 358 342 quinupristin 149 146 147 149 145 153 144 % impurities (A) 1.0 1.0 1.0 0.9 0.9 1.0 0.8 (B) 0.5 0.6 0.7 0.4 0.6 0, 6 0.5 (C) 0.2 0.1 0.2 0.1 0.1 0.1 0.1 (D) 0.5 0.5 0.5 0.4 0.4 0.5 0.3 (E) 0.3 0.2 - 0.1 0.2 0.1 0.1

Stability study of dose 1b over 24 months at 4 ° C

Table II

Dose la TO 6 months 9 months 12 months 18 1 months 24 months Test (mg / bottle) Dalfopristin 349 340 343 343 340 340 quinupristin 148 144 146 142 143 142 % impurities (A) 1.0 0.8 0.8 0.9 0.9 0.8 (B) 0.5 0.6 0.4 0, 6 0.4 0.5 (C) 0.2 0.2 0.1 0.2 0.1 0.2 (D) 0.4 0.4 0.4 0.4 0.4 0.3 (E) 0.1 - 0.2 0.2 0.2 0.1

Results of stability test of concentrated solution obtained from lyophilisate (premix)

Table III

premix TO 15 minutes 30 minutes 45 minutes 60 minutes Test (% relative to TO) Dalfopristin 100.0 99.7 100.2 99.0 99.0 quinupristin 100.0 100.2 100.7 99, 6 101.1 % impurities (A) 0.74 0.89 1.02 1.12 1.28 (B) 0.51 0.62 0.69 0.72 0.78 (D) 0.47 0.49 0.46 0.53 0.61 Some other impurities 0.28 0.30 0.32 0.33 0.38

Results of stability test of infusion solutions

For the stability test of dilutions under clinical conditions [500 mg of lyophilized quinupristine / dalfopristin (30/70) diluted in 250 ml of 5% glucose], three doses of the lyophilisate prepared as indicated (dose 1c, dose iid, dose le) are used. .

Stability of diluted solutions for infusion for 72 hours at 4 ° C.

Table IV

Test dose dose lc dose ld dose le TO 72 hours at 4 ° C TO 72 h at 4 ^e C TO 72 h at 4 ^e C (mg / 250 ml) Dalfopristin 313 297 314 301 318 306 quinupristin 135 127 134 129 136 131 % impurities (A) 1.5 4.2 1.1 4.1 1.6 4.5 (B) 0.7 0.9 0.6 0.8 0.8 1.0 (C) 0.2 0, 3 0.1 0.3 0.2 0.3 (D) 0.3 0.4 0.4 0.5 0.4 0.4 (E) 0.3 0.3 0.2 0.2 0, 6 0.3

Stability of diluted solutions for infusion for 6 hours at room temperature

Table V

Test dose dose lc dose ld dose le TO 6 hr temp. m. TO 6 hr temp. m. TO 6 hr temp. m. (mg / 250 ml) Dalfopristin 314 304 321 311 319 1 313 ' quinupristin 134 132 137 136 137 136 % impurities (A) 1.3 4.5 1.1 4.2 1.7 4.7 (B) 0.7 0.8 0.6 0.7 0.6 0.7 (C) 0.2 0.5 0.2 0.4 0.2 0.5 (D) 0.2 0.3 0.3 0.4 0.2 0.3 (E) 0.3 0.3 0.2 0.2 0, 3 0.3

Example 2

125 mg of the quinupristine / dalfopristine solution (30/70) at pH 4.50 in the form of a salt with hydrochloric acid or methanesulfonic acid are prepared according to the following procedure:

350 g of water for injection are introduced into the beaker. 30.0 g of quinupristine are dispersed in water at room temperature using a mechanical stirrer. Methanesulfonic acid or hydrochloric acid is added until dissolution is complete and until pH 4.50 is reached. 70.0 g of dalfopristin are dispersed in water using a mechanical stirrer, and then a 1N solution of methanesulfonic acid or hydrochloric acid is added until the dissolution is complete and pH 4.50 is reached. Homogenization is carried out for 10 minutes.

Make up the solution to 0.8 liters (824 g) with water for injectables.

By lyophilizing the solution according to the procedure described in Example 1, a lyophilisate is obtained which has good storage stability. A stability study at 4 ° C and room temperature confirms the good stability of the formulation (see Tables VI and VII).

Stability of methanesulfonic acid-based lyophilisates for 1 year at 4 ° C and room temperature:

Table VI

Methanesulfonic acid TO 6 months 9 months 1 year 4 C temp. m. Low: 14 ° C temp. m. 4 ⁶ C temp. m. Test (mg / container) Dalfopristin 332 332 299 328 ’319 324 310 quinupristin 143 150 135 149 145 146 143 % impurities (A) 3.7 4.0 3.9 3.4 3.3 4.3 4.4 (B) 1.9 1.7 1.7 1.6 2.2 1.9 2.8 (C 0.3 0.5 0.9 0.3 0.3 0, 3 0, 3 (D) 1.4 1.4 1.5 1.2 1.2 1.4 1.4

Stability of hydrochloric acid-based lyophilisates for 6 months at 4 ° C and at room temperature:

Table VII

Hydrochloric acid TO 6 months Low: 14 ° C temp. m. Test (mg / container) Dalfopristin 327 333 313 quinupristin 156 150 145 % impurities (A) 1.7 1.6 1.4 (B) 1.6 1.6 2.4 (C) 0.3 0.2 0.2 (D) 0.9 0.4 0.4

Example 3

125 mg quinupristine / dalfopristine (30/70) solutions are prepared according to Example 1 or Example 2 at different pH values by adding different amounts of 1N methanesulfonic acid; these solutions are intended for lyophilization or freezing. The pH of the lyophilization solutions is adjusted to 4.5-4.8. The pH of the solutions to be frozen is adjusted to 3.5 to 4.5.

The stability study of the lyophilisate batches (prepared under the dissolution conditions of the active ingredients described in Example 1, but at 600 ml by introducing 150 ml of water and 35-50 ml of 1N methanesulfonic acid solution before dispersing the active ingredients) shows that the composition is optimally stable over 4 years. (see Table VIII).

Stability of lyophilisates at pH range 4.3 to 4.8 for 4 years at 4 ° C.

Table VIII

dose 3a pH = 4.3 dose 3b pH = 4.5 dose 3c * pH - 4.7 dose 3d pH = 4.8 TO 4 years TO 4 years TO 4 years TO 4 years Test (mg / container) Quinupristine 175 148 159 154 152 153 159 149 dalfopristin 384 291 343 313 331 321 351 328 % impurities (A) 0, 6 0.5 0.6 0.8 0.8 0.9 1.1 1.1 (B) 1.0 3.3 0.8 2.1 0.9 1.2 1.0 1.1 (C) 0.5 0.5 0.4 0.4 0.4 0.4 0.3 0.5 (D) 0.8 0.7 0.9 0.6 0.7 0, 6 0.8 0.5

* batch prepared by adjusting pH by adding 6.5 ml of 0.5 N sodium hydroxide (under the conditions described in Example 5)

Stability of the freezing solutions prepared under the conditions described in Example 2 (see Table IX)

Table IX

dose 3e pH = 3.5 dose 3f pH = 4.0 dose 3g pH = 4.5 (1) (2) (3) (D (2) (3) (D (2) (3) Test (mg / container) Quinupristine 147 148 152 147 153 148 144 136 144 dalfopristin 339 328 335 320 336 331 334 313 334 % impurities (A) 2.0 1.9 2.0 1.8 1.8 2.0 2, 6 3.3 3.6 (B) 0.9 1.1 1.3 1.0 1.0 1.6 1.0 1.5 1.7 (C) 0.3 0.3 0.3 0.3 0.4 0.4 0.2 0.4 0.2 (D) 0.9 1.0 1.1 1.1 1.0 1.0 1.4 1.4 1.4

(1) after dissolution (2) after filtration (3) before freezing

Example 4

According to Example 1, quinupristine / dalfopristine (30/70) solutions were prepared at pH 4.75 and at various concentrations between 125 mg / ml and 250 mg / ml. These solutions are used to prepare 500 mg of lyophilisates. The use of the most concentrated solutions (200 and 250 mg / ml) is slower due to the dissolution time of dalfopristin and the pH adjustment time. The study shows that the degradation profile is not adjusted during the preparation, only the re-dissolution time of the lyophilisates is longer with increasing concentration of solutions (see Table X)

Degradation profile of solutions during preparation (after filtration and lyophilization)

Conditions for redissolving the lyophilisate

Table X

dose 4a 125 mg / ml dose 4b 143 mg / ml dose 4c 167 mg / ml dose 4d 200 mg / ml dose 4e 250 mg / ml d) (2) d) (2) (D (2) (D (2) (D (2) % impurities (A) 1.10 0, 99 0.66 1.13 0.58 0.74 0.54 0.58 0, 38 0.56 (B) 0.78 0, 83 0, 61 0, 92 0.58 0.72 0, 65 0.76 0.52 0.80 (C) 0.26 0.25 0.24 0.28 0.24 0.29 0.25 0.26 0.24 0.24 (D) 0.52 0, 55 0.58 0, 60 0.58 0, 62 0, 54 0.62 0.49 0, 51 Overall known impurities 2.66 2.62 2.09 2.93 1.98 2.37 1.98 2.22 1.63 2.11 Totally unknown impurities 2.38 2.37 2.18 2.22 2.27 2.44 2.29 2.13 2.24 2.09 Total impurities Redissolve 5.04 4.99 4.27 5.15 4.25 4.81 4.27 4.35 3, 87 4.20 Dissolution time in 4 ml of 5% glucose 40 p " 50 s 50 s - 2.5 min 3 min pH of the solution in 4 ml 5% glucose 4.54 4.56 4.56 4.55 4.44

(1) solution after filtration (2) Lyophilisate (T12H)

Example 5

According to Example 1, 125 mg / ml quinupristine / dalfopristine (30/70) solutions are prepared, their pH is adjusted to 4.75 with different amounts of 1N methanesulfonic acid (1-9 ml / L), and

I _t

0.5N sodium hydroxide (0-15 ml / l).

Conditions for pH adjustment (per liter of solution)

Table XI

dose 5a dose 5b dose 5c dose 5d dose 5e dose 5f Starting amount of methanesulfonic acid (g / l) 16.36 16.36 16.36 16.36 16.36 16.36 PH correction Add 1N methanesulfonic acid (ml / l) 1.0 2.0 4.0 4.4 8.0 9.0 Add 0,5N sodium hydroxide (ml / l) 0 0 7.0 6.2 15.0 14; 0

The stability of the prepared solutions (at 3 ° C for 20 hours) shows no difference depending on the pH adjustment conditions.

Stability of prepared lyophilisates:

«Μ m m Λί>

Ό

n ' ^a ABOUT φ ⁰ * * cn k © ^B o «R cn m ” ih cn «O ° m r * (D ⁰ * H about ^e O ih cn

VO 00 m σι rh cn σ » CM en CM * * about about ABOUT about ABOUT rh XT CM en CM about 00 CM cn CM The The rh about about about about

CM Η kO Γ * rH (Π rH αο r * cnσ>

cn m η cnη ***** ο ο οο ο Ε- »ω σι * X νο ω β · rH (Π

o o en rh about 10 CM cn CM x rh about ABOUT about about

Ό ιη ω

> 'Φ Ό

<n φ E n ABOUT 0 O <n IN) at Φ E about rh cn WHAT about Φ about E χτ

οο r * ο m m γη m * τ CM rH Π

ΙΟ H rH CH cn κο * H n cn m m i-ι m o

Eco r ~ *.

CM 00 m tn - <n

00 00 kO about k0 r * en CM t-t The H κ about ABOUT ABOUT about ABOUT

m k0 σι σι r * CD CD CM cn rh * The The about ABOUT about about about

k0 cn about m r * m CM en rh h H H about about ABOUT ABOUT ABOUT

cn σι k0 10 00 CM en rh about about ABOUT about ABOUT

Λ m <o>

• σ

co Φ ABOUT 0 ε ABOUT en m co Φ U 0 E about rh cn (0 about Φ E about XT en

m 00

K K m m rH cn ω σ *

ΓΊ 00 m m rH m m

k m xr in io rH cn * * * T r-1 L Ô 10 rH Cn

ε m C .H + J C * H4J 4J \ WHAT <0 <o σ> • H • H 4J E M M <0 and and • H with about > υ 4J C <M φ WHAT • H R-1 C Φ £ <Q E-> U Q

rH rH Γ- K r r * σι CM rH o o o o o

00 r * CM and en 00 r * CM rh H % The in ABOUT about ABOUT about ABOUT

ro m inin r * g * r <ni-i o o oo

00 rh en about WHAT lD CM rh The The The about ABOUT ABOUT about ABOUT

Example 6

Frozen quinupristine / dalfopristine (30/70) solutions in the form of a salt with methanesulfonic acid or hydrochloric acid are prepared in a concentration range of 5 to 20 mg / ml and at pH

3.5 to 5.0 and in the presence of an isotonizing agent such as sodium chloride and glucose. The stability of the solutions stored in frozen form has been found to be satisfactory.

(a) 800 g of water for injectables are introduced into a dissolver of a vessel equipped with a cooling unit. The solution is cooled to between 0 and 6 ^e C during preparation. 98% of the amount of methanesulfonic acid required to dissolve and adjust the pH is added. 1.5 g of quinupristine are added and dissolved with stirring with a mechanical stirrer, 3.5 g of dalfopristine are added and dissolved with stirring with a mechanical stirrer. The solution is isotonized with glucose. The pH of the solution was adjusted to 5.0 with 0.1N methanesulfonic acid solution. make up this solution to 1 liter with injection water.

Stability of the dose prepared according to procedure (a) for 3 months at - 22 ° C

Table XIII

TO 3 months Test (mg / ml) dalfopristin 3.37 3.38 quinupristin 1.41 1.37 % impurities (A) 2.42 2.55 (B) 0.32 0.37 (C) 0.18 0.29 (D) 0.32 0.37 (E) - 0.12

(b) The solution was prepared as described above, but introducing 6 g of quinupristine and 14 g of dalfopristin. The pH is adjusted to 3.5 with a 0.1 N methanesulfonic acid solution. Make up the solution to 1 liter with water for injectables.

Stability of the batch prepared according to procedure (b) for 3 months at - 22 ° C

Table XIV

TO 3 months Test (mg / ml) dalfopristin 14.0 16.8 quinupristin 5.5 6.6 % impurities (A) 0.29 0.74 (B) 0.26 0.30 (C) 0.27 0.28 (D) 0.31 0.40

(c) The solution was prepared as described in process (a), isotonicated with sodium chloride and the pH adjusted to 3.5 with 0.1N methanesulfonic acid. Make up the solution to 1 liter with water for injectables.

Stability of the dose prepared according to procedure (c) for 3 months at - 22 ° C

Table XV

TO 3 months Test (mg / ml) dalfopristin 3.57 3.90 quinupristin 1.42 1.57 % impurities (A) 0.25 0, 56 (B) 0.20 0.21 (C) 0.21 0.15 (D) 0.30 0.35

(d) The solution is prepared as described in process (c), but the pH is adjusted to 5.0 with a 0.1N hydrochloric acid solution. Make up the solution to 1 liter with water for injectables.

Dose stability according to procedure (d) for 3 months at - 22 ° C

Table XVI

TO 3 months Test (mg / ml) dalfopristin 3.41 3.89 quinupristin 1.45 1, 63 % impurities (A) 2.77 2, 64 (B) 0.32 0.35 (C) 0.21 0.15 (D) 0.32 0.37

Claims (13)

PATENT CLAIMS A stabilized pharmaceutical composition based on a quinupristine / dalfopristin mixture, characterized in that it comprises at least a stoichiometric amount of methanesulfonic acid or hydrochloric acid and the pH of the composition is in the range of 3.5 to 5. Stabilized pharmaceutical composition according to claim 1, characterized in that it can be in a lyophilized, frozen or liquid state. A stabilized pharmaceutical composition according to any one of claims 1 or 2, characterized in that it comprises: Dalfopristin and quinupristin; Methanesulfonic acid or hydrochloric acid in at least stoichiometric amounts relative to the total amount of dalfopristin and quinupristin; If appropriate, an excess of methanesulfonic acid or hydrochloric acid to adjust the pH of the solution to between 3.5 and 5; Optionally an isotonizing agent and / or other pharmaceutically acceptable excipient; The amount of water suitable to adjust the concentration of the solution, and in the case of the lyophilisate, the water is removed. Stabilized pharmaceutical composition according to claim 3, characterized in that the concentration of the active ingredient quinupristine / dalfopristine is between 5 and 250 mg and, as regards the lyophilisate, the proportion of active ingredient is 5 to 95%. The stabilized pharmaceutical composition according to claim 4, wherein the concentration of the active ingredient quinupristine / dalfopristine in the lyophilisate is between 20 and 90%. Stabilized pharmaceutical composition according to any one of claims 1 to 4, characterized in that its pH ranges from 3.5 to 4.5. A stabilized pharmaceutical composition according to claim 6 having a pH of 3.5. Stabilized pharmaceutical composition according to any one of claims 1 to 4, characterized in that its pH ranges from 4.5 to 5. A process for the preparation of a ready-to-use stabilized solution, characterized in that it is obtained from the lyophilized or frozen pharmaceutical composition according to claim 2. A process for the preparation of a pharmaceutical composition according to claim 1, characterized in that quinupristine, dalfopristine, methanesulfonic acid or hydrochloric acid are simultaneously or sequentially dissolved in water and then the pH is adjusted to a range of 3.5 to 5. Process for the preparation of a pharmaceutical composition according to claim 10, characterized in that quinupristine and then dalfopristine are dissolved successively in water acidified with methanesulfonic acid or hydrochloric acid and then the pH is adjusted to a range of 3.5 to 5. A method according to any one of claims 10 or 11 for the preparation of a pharmaceutical composition according to claim 2, characterized in that the prepared solution is lyophilized or frozen, if appropriate. Use of methanesulfonic acid or hydrochloric acid for the preparation of stabilized pharmaceutical compositions according to any one of claims 1 to 8.